Admission for and mortality from primary venous thromboembolism in women of fertile age in Denmark, 1977-95
The third generation oral contraceptive controversy
Researchers from Denmark in this week's BMJ report the findings of their study which show an increase in admission rates of women for venous thromboembolism. They say that this rise seems to correlate with the increase in the use of third generation oral contraceptives.
Dr Lene Mellemkjr from the Danish Cancer Society and colleagues investigated all admissions (male and female) in Denmark for people aged 15 -49 years between 1977-93 with a registration of pulmonary embolism, deep venous thrombosis and other embolotic or thrombotic disorders. They studied admission levels in the context of the use of third generation pills representing 0.2 per cent of total use of oral contraceptives in 1984; 17 per cent in 1988; 40 per cent in 1990 and 66 per cent in 1993.
They found that admission rates for primary venous thromboembolisms among women fluctuated around 120 per million person years during 1977-88, but increased to about 140 per million person years during 1989-93. For men, the admission rates remained stable throughout the period at a rate similar to that for women in recent years.
Mellemkjr et al cautiously interpret this as support for the hypothesis that third generation oral contraceptives increase the risk of venous thromboembolism to a greater extent than second generation oral contraceptives. They say that the increase in admissions, although small, could not be explained by changes in diagnostic procedures or in the threshold for admission, since no increase was seen among men.
In a linked editorial, Dr Paul O'Brien from Parkside Health NHS Trust in London echoes Mellemkjr et al's caution. He says that the increased risk of venous thrombosis with third compared with second generation pills is real but that it is small in absolute terms, although greatest in women starting to take the pill [overall estimates from the Medicines Commission are 15 per 100,000 women per year in second generation pill users and 25 per 100,000 women on third generation pills, which is smaller than that associated with pregnancy, which has been estimated at 60 cases per 100,000 pregnancies]. He also says that the causation implied in Mellemkjr et al's study requires stronger evidence.
However, O'Brien also writes that four previous well designed studies found that third generation pills had double the risk of thrombosis of second generation pills. He says that these studies have been subjected to relentless criticism for being flawed but, he says, these criticisms have failed to explain the excess risk. He also says that subsequent studies have "…generally been of lower methodological quality and have had variable results… ." "…In a $3bn world contraceptive market the stakes are high" writes O'Brien.
O'Brien believes that clinical evidence indicates that second generation contraceptives should be the first choice for women. He says that the potential benefits of the less androgenic (ie less prone to produce masculine characteristics) third generation pills, such as reduced acne, are yet to be proved but, if present, for some women these benefits may outweigh the small extra risk of thrombosis. He concludes that "It is not that third generation contraceptives are unsafe - it is just that we have something safer."
Contact:
Dr Paul O'Brien, Senior Clinical Medical Officer in Clinical Effectiveness, Services for Women, Parkside Health NHS Trust, St Charles Hospital, London
Email: PaulOBrien@care.prestel.co.uk
Dr Lene Mellemkjr, Research Fellow, Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen Denmark
Email: lene@cancer.dk
lene@cancer.dk